Point of Care Ultrasonography for the Septic Patient in the Emergency Department: A Literature Review

The point-of-care ultrasound (POCUS) has been effectively used in intensive care units for the management of septic patients. Since it is a time- and cost-effective non-invasive imaging modality, its use in the emergency department (ED) has been advocated for by medical experts. This review summarizes the existing literature regarding the breadth of POCUS as a supplementary tool to the holistic approach of septic patients in the ED setting. A literature search was conducted via PubMed (MEDLINE), Cochrane Library, and Scopus databases, analyzing studies which examined the use of POCUS in the ED for non-traumatic, septic, and/or undifferentiated hypotensive patients, resulting in 26 studies. The first cluster of studies investigates the efficiency of POCUS protocols in the differential diagnosis and its reliability for distributive/septic shock and sepsis management. In the second cluster, POCUS use results in faster sepsis cause identification and improves therapeutic management. The third cluster confirms that POCUS aids in the accurate diagnosis and management, even in rare and complicated cases. The results of the present review support the well-documented utility of POCUS and highlight the importance of POCUS incorporation in the comprehensive management of the septic patient in the ED setting.


Introduction
Sepsis is a medical emergency and a life-threatening disorder, which imposes a major health burden on emergency departments (EDs) and intensive care units (ICUs), accounting for a significant proportion of in-hospital and ICU mortality [1]. In a recent analysis of the Global Burden of Disease, Injuries, and Risk Factors (GBD), sepsis morbidity and mortality is estimated to 48.9 million global cases and 11 million deaths, or 1 in 5 deaths worldwide. Of the 48.9 million cases, 33.1 have occurred in patients with an underlying infectious condition and the remaining 15.8 million in individuals with underlying injuries or non-communicable diseases (NCD) [2]. Although the initial interest on sepsis has been focused in the ICU setting, attention has been gradually shifted towards the ED field, since it has been recognized that the early initiation of treatment in the ED [3], ideally within one hour from the diagnosis of sepsis, is crucial in order to decrease length of stay, morbidity, and mortality [4].
To this end, point-of-care ultrasonography (POCUS) has emerged as an adjunct imaging modality for the management of the septic patient upon arrival to the ED. POCUS allows for fast, real-time assessment of cardiovascular, respiratory, or other acute pathologies. Moreover, as an extension of physical examination and in conjunction with additional testing, it narrows differential diagnosis. In this way, it enhances the initial management plan and it shortens the time to clinical decision-making. Apart from its diagnostic value, POCUS can also provide information regarding a patient's response to treatment when serially performed [5,6]. In the 1990s, emergency medicine (EM) physicians in the United States of America advocated for the use of POCUS in the ED, so POCUS nowadays is a standard component of EM residency training programs [5]. In light of the recognition of the usefulness of POCUS in EM, several ultrasound protocols have been developed and implemented. The most well-known and widely used protocol for non-traumatic patients is the rapid ultrasound in shock (RUSH) exam, which helps clinicians differentiate various etiologies of shock in a short period of time [6][7][8].
Considering the enormous sepsis-induced burden on health care systems [2], in conjunction with the complex nature of sepsis-associated causes and symptoms, it is obvious that the integration of methods and techniques for early diagnosis and management of sepsis in the ED is not just useful, but also of critical importance. In view of the aforementioned facts, the aim of this manuscript is to review the existing literature regarding the breadth of POCUS use and its contribution to the prompt diagnosis and effective management of septic patients in the ED setting. Specifically, the present review focuses on the existing data with reference to the utility and reliability of multimodal POCUS for non-invasive differential diagnosis of shock, rapid identification of the septic source, and treatment guidance.

Materials and Methods
A literature review was conducted using the online databases PubMed (MEDLINE), Cochrane Library, and Scopus. In our search strategy, the publication period under consideration was defined from 2010 to July 2022, excluding all grey literature. In addition to the database search, the cited bibliography of the selected articles was reviewed in order to ensure that no significant relevant research data were missed.
Three reviewers worked independently to review all eligible titles and abstracts, and by using inclusion criteria, defined a priori. These criteria were: publication language (English), time of publication (2010-July 2022), aim (assessment of POCUS use in the ED for non-traumatic, septic, and/or undifferentiated hypotensive patients), and research type, namely randomized clinical trials (RCTs), observational studies (including both prospective and retrospective cohorts), and case reports. After initial selection, the reviewers read the full text to determine whether inclusion criteria were met.

Results
Initial search resulted in a total of 58 articles, with 32 being eligible for review. After reading the full text, 6 more articles not meeting inclusion criteria were excluded. Eventually, 26 articles  were included in the final analysis ( Figure 1).

Discussion
Although sepsis represents one of the main causes of ED admission, its incidence remains underestimated because it constitutes an intermediate and not a primary cause of illness and death [2]. In the present review, the studies included in the first cluster demonstrate that the incidence of sepsis remains high, yet widely variable. Specifically, three [9,11,12] out of nine studies present the frequency of septic shock in the ED (3.6%, 12%, and 13.5%, respectively), while four [10,13,15,17] report the overall incidence of inhospital sepsis (52%, 32%, 22.2%, and 55.5%, respectively). All these studies emphasize the importance of recognizing sepsis early in the clinical course, while consistently adopting a systematic evidence-based bundle of care and implementing it in a timely manner. Indeed, this approach is corroborated by recent sepsis guidelines [4].
Almost all studies from the first cluster conclude that the use of POCUS contributes to the early differential diagnosis, either of the cause of hypotension, or the cause of signs and symptoms that are suggestive of shock regardless of systolic blood pressure. This notion is even supported by Atkinson et al. [10], although their RCT failed to demonstrate any survival benefit conveyed by the use of POCUS in ED patients with shock and undifferentiated hypotension. In addition, in four out of nine studies, the addition of POCUS to standard ED care yielded a narrower and more accurate list of possible causes of nontraumatic undifferentiated hypotension, as evidenced by the reliability indices displaying agreement between the initial working diagnosis (based on combined clinical and POCUS evaluation) and the final diagnosis. Indeed, with regard to distributive shock, the combined clinical and POCUS diagnosis demonstrates high agreement with the final diagnosis (as measured by Kappa coefficient-k, ranging from 0.71 to 1.00), while it shows very good sensitivity (63.6-75%), as well as excellent specificity (99.7-100%), positive predictive value (87.5-100%), and negative predictive value (86.1-100%) [9,[11][12][13] (Table 4). Two key points of these studies are worth mentioning. First, when implementing RUSH protocol, serial examinations are needed in cases of suspected septic shock [12]. Second, sepsis is a form of distributive shock that can be promptly diagnosed through identification of the sepsis source with the use of POCUS; multimodal POCUS can reveal multiple "foci of sepsis", such as consolidation, air bronchogram, gallbladder wall thickening, limb cellulitis, hypoechoic pancreas, and vegetations [13]. Furthermore, Sasmaz et al. [15] and Volpicelli et al. [17] have reported perfect total agreement between the preliminary (ultrasonographybased) and final diagnosis (k = 0.82 and k = 0.838 respectively, p < 0.001 in both). In the latter study, ultrasonography-based diagnosis for distributive shock was accurate in 35 of 40 patients (87.5%). In conclusion, the contribution of POCUS to the early diagnosis of nontraumatic undifferentiated hypotension in ED patients is almost indisputable. Even in the sole study with contradictory results, which reports that POCUS use in the ED prior to a key intervention was associated with a higher mortality rate in critically ill patients [14], the authors admit potential sources of bias against POCUS. In fact, their registry does not include patients who were resuscitated in the ED. On top of that, the proportion of patients with diagnostic uncertainty, who were eventually identified as critically ill with the use of POCUS, is not taken into account.
The second cluster of studies [18][19][20][21][22] acknowledge the contributing role of POCUS in determining the source and guiding the management of sepsis. Considering the complex nature of sepsis, the results are really promising. According to a study by Cortellaro et al., in 89% of the cases, POCUS enhanced emergency physicians' (EP) ability to identify the cause of sepsis; moreover, POCUS-based diagnosis was achieved in an expedited manner (10min), with great accuracy (75%) and sensitivity (73%) [18]. Furthermore, the use of POCUS has been shown to be beneficial in terms of guiding fluid administration and achieving hemodynamic improvement in 97.4% of ED patients with septic shock [19]. In the study of Haydar et al., it was demonstrated that the use of POCUS facilitated clinical decision-making by increasing EPs' certainty in 71% of the cases and by leading to the revision of overall treatment plans in 53% of the cases (change of the presumed cause in 17% and modification of the procedural intervention plans in 27%) [20]. However, a recent RCT assessed the effect of ultrasound-guided fluid management (UGFM) in patients with septic shock and showed no significant difference in 30-day mortality between patients receiving usual care and patients of the UGFM group, even though the latter group were administered less amount of resuscitation fluid [21]. Finally, the fourth study of this cluster [22] pointed out the high prevalence of sepsis in ED patients with acute circulatory failure (ACF) and verifies the preponderance of hypovolemia and vasoplegia in septic patients. This study showed that focused cardiac ultrasounds (FOCUS) could promptly identify left or right ventricular systolic failure in 31% of septic patients. Additionally, the study depicted that, even recently trained in ultrasounds, EPs were able to properly identify ACF mechanisms, achieving high agreement with the interpretation of ultrasound findings by ICU experts. Therefore, early FOCUS assessment can serve as a guide to fluid resuscitation in septic patients presenting to the ED with ACF. Similar promising results have emerged from the third cluster of studies, which included case reports. POCUS was found to be a supportive tool for early and accurate diagnosis and overall management in complex septic cases. Three of the POCUS-based diagnoses involved the cardiovascular system (acute heart failure with reduced ejection fraction, severe aortic stenosis, and mitral regurgitation [23]; myocardial infarction caused by endocarditis-related septic embolization [26]; methamphetamine-associated cardiomyopathy [30]). In the latter case, POCUS set the diagnosis, dictated the appropriate restriction in the administration of intravenous fluids, and guided proper consultation. Two cases involved the respiratory system. The first one was a ruptured pulmonary hydatid cyst, in which case POCUS directed EPs towards a timely and proper diagnosis, hence enabling appropriate management of the underlying septic and anaphylactic shock while prompting definitive surgical intervention [29]. The second one was an unexpected empyema revealed by POCUS in a patient being treated for community-acquired pneumonia [33]. Both of these cases confirm the utility of POCUS, not only in diagnosing pneumonia, but also in identifying associated complications, such as pleural effusions or empyema. Accordingly, POCUS is proposed as a valuable tool in the ED setting for patients with undifferentiated dyspnea and sepsis. Four cases dealt with various other clinical entities, namely esophageal perforation [27], obstructive uropathy causing moderate kidney hydronephrosis [25], xanthogranulomatous pyelonephritis [28], and liver abscess [34]. Regarding esophageal perforation, deterioration and death due to sepsis can occur within hours of presentation. Likewise, obstructive pyonephrosis has a mortality rate of 40% if not addressed in a timely manner, while pyogenic liver abscess is also accompanied by high mortality if not diagnosed promptly. In all previous four cases, POCUS imaging played a pivotal role in the accurate diagnosis of the sepsis cause. Finally, two case reports and a retrospective case series analysis involved the musculoskeletal system: necrotizing fasciitis of the left inner thigh, diagnosed via RUSH protocol [24]; glenohumeral joint septic arthritis and subdeltoid septic bursitis, in which case musculoskeletal POCUS was diagnostic through ultrasound-guided needle aspiration [32]; and septic arthritis of the hip diagnosed via POCUS and treated with aspiration in the ED in a series of 17 children [31].
All the aforementioned studies emphasize the utility of POCUS in the ED, highlighting its role as a time-and cost-effective, accurate, and non-invasive diagnostic imaging modality. With the focus on septic patients and their complex pathology, a systematic effort is warranted in order to develop integrated protocols [8,9], algorithms [25], and guidelines. The objective is to facilitate the rapid and holistic assessment of patients in the ED, readily identify the source of sepsis or the cause of undifferentiated hypotension, and further guide the resuscitation process. A recent review summarizes the application of an integrated bedside ultrasound multiorgan approach in septic patients as an adjunctive tool to clinical examination and laboratory studies. Its use is not only supported for the diagnosis of septic shock and for the identification of the culprit infection, but also for the assessment of fluid responsiveness, resuscitation effectiveness, and guidance of diagnostic procedures and infectious source control [35].
This review depicts the limited number of studies regarding the use of POCUS in ED septic patients when compared with similar studies in the ICU setting, which is the main limitation of the study. These available studies have shown diversity in terms of cohort size and characteristics, POCUS parameters evaluated, and outcome elements that have been measured. However, even though POCUS is an established imaging modality in the ED for multiple time-sensitive, critical diseases such as trauma or cardiac arrest and it is already incorporated in universal guidelines, it seems that there is a delay in the integration of POCUS in international sepsis guidelines.

Conclusions
The results of the present review support the well-documented utility of POCUS and highlight the importance of POCUS incorporation in the comprehensive management of the septic patient in the ED setting. At the same time, literature remains limited in terms of large scale, multi-center studies focused only in septic patients presented to the ED. Further development of research studies, alongside with integration of POCUS use in sepsis guidelines, will strengthen and extend its use in everyday clinical practice.
Author Contributions: E.P. conceived, designed and coordinated the study; D.M., S.B. and C.V. contributed to the data acquisition, analysis and interpretation; C.V. drafted the manuscript and contributed to the final layout of the tables and figure; E.P. and I.V. provided fundamental guidance; J.P. and I.V. performed editing and critical revision of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest:
Verras, Ventoulis, Bezati, Matsiras and Polyzogopoulou have no conflicts of interest or financial ties to disclose. Parissis received honoraria for lectures from Orion pharma, Pfizer, Servier, Astra, AO Orphan and Roche Diagnostics.